Carbazole derivatives

ABSTRACT

A compound of the formula (I): 
     
         ArCH.sub.2 R.sup.1 
    
     where Ar is ##STR1## where Z is NH, NCH 3  or NEt and R 1  is an hydroxyalkylamino group and pharmaceutically acceptable salts thereof. The compounds are useful as antitumor agents.

This is a divisional of copending application Ser. No. 07/132,724 ,filed on 12/11/87, now Pat. No. 4,866,070; which is a continuation ofSer. No. 06/801,085, filed 11/22/85 which is a continuation-in-part ofSer. No. 06/673,355, filed 11/20/84 both now abandoned.

The present invention relates to heteropolycyclic alkanol derivativeswhich have been found to have biocidal activity. More specifically theinvention concerns aminoalkanol derivatives containing aheteropolycyclic ring system, methods for the synthesis thereof, novelintermediates therefor, pharmaceutical formulations thereof and the usethereof as biocidal agents, particularly antitumor agents.

Accordingly, in a first aspect, the present invention provides acompound of the formula (I)

    ArCH.sub.2 R.sup.1                                         (I)

or a monomethyl or monoethyl ether thereof (the compound of formula (I)including these ethers may contain no more than 29 carbon atoms intotal); ethers, esters thereof; acid addition salts thereof; wherein Aris a fused tricyclic aromatic ring system containing a maximum of 14ring atoms and at least one heteroatom or a fused pentacyclic ringsystem with at least four aromatic rings containing a maximum of 22 ringatoms and at least one heteroatom; either ring system optionallysubstituted by one or two substituents (the substituents will containnot more than four carbon atoms in total when taken together being thesame or different and are selected from halogen; cyano; C₁₋₄ alkyl orC₁₋₄ alkoxy, each optionally substituted by hydroxy or C₁₋₂ alkoxy;halogen substituted C₁₋₂ alkyl or C₁₋₂ alkoxy; a group S(O)_(n) R²wherein n is an integer 0, 1 or 2 and R² is C₁₋₂ alkyl optionallysubstituted by hydroxy or C₁₋₂ alkoxy; or the ring system is optionallysubstituted by a group NR³ R⁴ containing not more than 5 carbon atomswherein R³ and R⁴ are the same or different and each is a C₁₋₃ alkylgroup or NR³ R⁴ forms a fiveor six-membered heterocyclic ring optionallycontaining one or two additional heteroatoms).

For either the tricyclic or pentacyclic ring system there is a maximumof one heteroatom for each ring present but preferably only one or twoof the rings contain a heteroatom.

The rings forming the tricyclic or pentacyclic ring system contain fiveor six atoms. The heteroatoms are conveniently nitrogen, phosphorus,oxygen, sulfur or selenium; suitably the heteroatom is oxygen, sulfur ornitrogen. The ring system should be planar or deviate only slightly fromplanarity. Suitably the tricyclic or the pentacyclic ring system isaromatic or contains one non-aromatic ring. Preferably the ring systemis aromatic. Nitrogen atoms contained in five-membered rings aresubstituted by hydrogen, methyl or ethyl.

R¹ contains not more than eight carbon atoms and is a group ##STR2##wherein m is 0 or 1; R⁵ is hydrogen;

R⁶ and R⁷ are the same or different and each is hydrogen or C₁₋₅ alkyloptionally substituted by hydroxy;

R⁸ and R⁹ are the same or different and each is hydrogen or C₁₋₃ alkyl;##STR3## is a five- or six-membered saturated carbocyclic ring; R¹⁰ ishydrogen, methyl or hydroxymethyl;

R¹¹, R¹² and R¹³ are the same or different and each is hydrogen ormethyl;

R¹⁴ is hydrogen, methyl, hydroxy, or hydroxymethyl.

Specific ring systems included within the scope of the present inventioninclude tricyclic ring systems such as ##STR4## wherein Z is aheteroatom, and pentacyclic ring systems containing four 6-memberedcarbocyclic aromatic rings and a 5-membered aromatic ring containing oneheteroatom; preferably the heteroatom in either ring system is O, S, NH,NCH₃ or NEt; ##STR5## preferably any of the ring systems is optionallysubstituted by one substituent.

Ar is suitably ##STR6## wherein Z=O, S, NH, NCH₃, NEt;

suitably ArCH₂ R¹ or a monomethyl or monethyl ether thereof contains notmore than 28 carbon atoms in total;

suitably R¹ is ##STR7## wherein R¹⁶ is CH₂ OH, CH(CH₃)OH or CH₂ CH₂ OH,R¹⁷ is hydrogen, C₁₋₃ alkyl or CH₂ OH,

R¹⁸ is hydrogen or methyl.

Preferably Ar is ##STR8## preferably R¹⁶ is CH₂ OH or CH(CH₃)OH; R¹⁷ ishydrogen, methyl, ethyl or CH₂ OH.

Most preferably R¹ is a diol of the structure ##STR9## wherein R¹⁹ ishydrogen or methyl and R²⁰ is hydrogen, methyl or ethyl, preferablymethyl.

Acid addition salts included within the scope of the present inventionare those of compound of formula (I) and ethers and esters thereof.Esters and nonpharmaceutically useful salts of the compounds of theformula (I) are useful intermediates in the preparatoin and purificationof compounds of the formula (I) and pharmaceutically useful acidaddition salts thereof, and are therefore within the scope of thepresent invention. Thus, acid addition salts of the compounds of theformula (I) useful in the present invention include but are not limitedto those derived from inorganic acids, such as hydrochloric,hydrobromic, sulfuric and phosphoric acids, and organic acids such asisethionic (2-hydroxyethylsulfonic), maleic, malonic, succinic,salicylic, tartaric, lactic, citric, formic, lactobionic, pantothenic,methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic,naphthalene-2-sulfonic, and ascorbic acids, and amino acids such asglycine.

Acid addition salts particularly useful as biocidal agents are thosethat are pharmacologically and pharmaceutically acceptable. Thus,suitable acid addition salts include but are not limited to thosederived from hydrochloric, methanesulfonic, ethanesulfonic, isethionic,lactic, and citric acids.

The preferred pharmacologically and pharmaceutically acceptable saltsare those that are soluble in solvents suitable for parenteraladministration, for example, hydrochlorides, methanesulfonates andisethionates.

Esters of compounds of formula (I) are derived from acids known to thoseskilled in the art to be suitable for ester formation, and areconveniently those derived from C₁₋₆ alkanoic acids or alkanoic acidderivatives, for example acetic acid, propionic acid, n-butyric acid andiso-butyric acid. The esters may be formed from all or only some of thehydroxy groups contained in the compounds of formula (I). Specificcompounds within the scope of formula (I) include;

2-[(1-Dibenzothiophenylmethyl)amino]-2-methyl-1,3-propanediol,

2-[(2-Dibenzothiophenylmethyl)amino]-2-methyl-1,3-propanediol,

2-[(4-Dibenzothiophenylmethyl)amino]-2-methyl-1,3-propanediol,

2-[(1-Dibenzofuranylmethyl)amino]-2-methyl-1,3-propanediol,

2-[(2-Dibenzofuranylmethyl)amino]-2-methyl-1,3-propanediol,

2-[(Naphtho[2,3-b]thiophen-4-ylmethyl)amino]-2-methyl-1,3-propanediol,

2-Methyl-2-[(naphtho[2,1-b]thiophen-5-ylmethyl)amino]-1,3-propanediol,

2-Methyl-2-[(naphtho[2,1-b]thiophen-2-ylmethyl)amino]-1,3-propanediol,

2-Methyl-2-[(naphtho[1,2-b]thiophen-2-ylmethyl)amino]-1,3-propanediol,

2-Methyl-2-[(naphtho[1,2-b]thiophen-5-ylmethyl)amino]-1,3-propanediol,

2-Methyl-2-[(naphtho[1,2-b]furan-2-ylmethyl)amino]-1,3-propanediol,

2-Methyl-2-[(naphtho[2,1-b]furan-2-ylmethyl)amino]-1,3-propanediol,

2-[(9-Acridinylmethyl)amino]-2-methyl-1,3-propanediol and

2-[(Acenaphtho[1,2-b]quinolin-10-ylmethyl)amino]-2-methyl-1,3-propanediol;ethers, esters thereof; acid addition salts thereof.

Of these specific examples of compounds of formula (I), the mostpreferred compound is2-[(naphtho[2,3-b]thiophen-4-ylmethyl)amino]-2-methyl-1,3-propanediol or2-[(1-dibenzothiophenylmethyl)amino]-2-methyl-1,3-propanediol; ethers,esters thereof; acid addition salts thereof. The compounds of formula(I) and their ethers, esters and salts thereof may be prepared by anymethod known in the art for the preparation of compounds of analogousstructure. Thus, the compounds of formula (I) may, for example, beprepared by any of the methods defined below.

1. The reduction of a compound of formula (II) ##STR10## Wherein R² -R⁴and R⁶ -R¹⁴ are as hereinbefore defined or a suitably protectedderivative thereof followed by deprotection where appropriate.

The conditions and reagents for such a reaction are well known to thoseskilled in the art, and any such conditions/reagents may be employed.The conversion of (II) or suitably protected derivatives thereof may becarried out by a reducing agent followed by deprotection if necessary.The reduction is conveniently carried out by a metal hydride such aslithium aluminum hydride, sodium borohydride, sodium cyanoborohydride,or by catalytic hydrogenation, conveniently by hydrogen in the presenceof a metal catalyst such as palladium or platinum, or equivalentreagents as outlined by J. March, Advanced Organic Chemistry, 2nd ed.,pages 819-820, McGraw Hill, New York, 1977. The reduction is suitablycarried out with the compound of formula (II) in solution in an inertsolvent or mixture of solvents compatible with the reducing agent, at anon-extreme temperature, for example, between 0° and 80° C.,conveniently at room temperature.

In the case of lithium aluminum hydride and like reagents, suitablesolvents include ethers (for example tetrahydrofuran, diethyl ether and1,2-dimethoxyethane) optionally in the presence of a hydrocarboncosolvent (for example toluene, benzene or hexane).

In the case of sodium borohydride and like reagents, suitable solventsinclude alcohols (for example ethanol, methanol or isopropanol)optionally in the presence of a hydrocarbon cosolvent (for exampletoluene, benzene or hexane) or an ether cosolvent (for example diethylether or tetrahydrofuran).

In the case of sodium cyanoborohydride and like reagents, suitablesolvents include those described for sodium borohydride and in thepresence of an acid conveniently glacial acetic acid or ethanolichydrochloric acid as outlined in, for example, R. Hutchins et al.,Organic Preparations and Procedures International 11, 201 (1979).

In the case of catalytic hydrogenation, suitable solvents includealcohols (for example methanol and ethanol) optionally in the presenceof a hydrocarbon cosolvent (for example toluene or benzene) or ethercosolvent (for example diethyl ether or tetrahydrofuran) in the presenceof an acid (for example glacial acetic acid or ethanolic hydrochloricacid) or in glacial acetic acid.

Protected derivatives of compounds of formula (II) are conveniently usedwhen lithium aluminum hydride is employed as the reducing agent.Convenient protecting groups are compatible with the reducing agentutilized and are readily removed under nondestructive conditions, forexample benzyl, tetrahydropyranyl and isopropylidene ethers.

It is often convenient not to isolate the compound of the formula (II)but to react a compound of the formula (III) with a compound of theformula (IV): ##STR11## wherein Ar and R² -R⁴ and R⁶ -R¹⁴ are as definedin (I), and reduce the compound of the formula (II) so formed in situ.The reaction of the compounds of the formulae (III) and (IV) is againsuitably carried out using conditions and reagents which are well knownto those skilled in the art, for example in the presence of an acid,such as a sulfonic acid, i.e., p-toluenesulfonic acid, in an appropriateinert solvent, such as an aromatic hydrocarbon, suitably toluene, withazeotropic removal of water followed by treatment with the reducingagent in an appropriate solvent, suitably ethanol or methanol.Alternatively, (II) formed under equilibrium conditions in appropriatesolvents can be reduced in situ with an appropriate reducing agent,suitably sodium cyanoborohydride. The compound of formula (III) may bein the form of a protected aldehyde, for example an acetal, whichliberates the aldehyde function under the reaction conditions.

In turn, a compound of formula (III) can be synthesized by reacting theappropriate heteropolycyclic ring with a formylating agent such as thatgenerated by the reaction between SnCl₄ and Cl₂ CHOCH₃ or equivalentreagents, for example, according to the method of A. Rieche et al.,Chem. Ber. 93, 88 (1960), or with other standard formylatingreagents/procedures known to the art, for example, the Gatterman-Kochreaction (CO/HCl/AlCl₃ /CuCl), the Gatterman reaction (HCN/HCl/ZnCl₂),and the Vilsmeier reaction (POCl₃ /PhN(Me)CHO, or POCl₃ /Me₂ NCHO) (J.March, vide supra, pages 494-497).

The compounds of the formula (III) may also be prepared from anappropriate heteropolycyclic ring substituted by a suitable functionalgroup such as (but not limited to) esters, CH₂ OH, CHBr₂, CH₃, COCH₃,COOH, or CN, and converting this functional group to an aldehyde groupby methods well known to those skilled in the art.

Where the heteropolycyclic ring bears substituents, the compound offormula (III) may be prepared by a variety of methods known in the artof organic chemistry depending on the nature of the substituent on theheteropolycyclic ring. For example, if the substituent(s) is a halogen,the starting materials may be prepared by direct treatment of theheteropolycyclic ring with a halogenating agent (e.g., Cl₂, Br₂, or SO₂Cl₂) or indirectly by such routes as the Sandmeyer reaction (H. H.Hodgson, Chem. Rev. 40, 251 (1947). If the substituent(s) is alkyl, theheteropolycyclic ring may be reacted with the appropriate reagents underFriedel-Crafts reaction conditions (G. A. Olah, Friedel Crafts andRelated Reactions, Vols. 1-3, Interscience, New York, NY, 1963-1965).

In appropriate cases, the compounds of the formula (IV) and ethersthereof also may be prepared by methods known in the art, for example,by the reaction of a compound of the formula (V) ##STR12## (or ethersthereof) wherein R⁷ -R⁹ and R¹¹ -R¹⁴ and m are as hereinbefore definedwith an appropriate aldehyde, conveniently acetaldehyde or formaldehyde(as in B. M. Vanderbilt and H. B. Hass, Ind. Eng. Chem. 32, 34 (1940))followed by reduction (as outlined in J. March, vide supra, pages1125-1126), conveniently by hydrogen and a metal catalyst (for example,a platinum containing catalyst) in an appropriate solvent, convenientlyglacial acetic acid.

2. The reduction of a compound of the formula (VI) ##STR13## wherein Arand R² -R¹⁴ are as hereinbefore defined and the hydroxy groups areoptionally protected, followed by deprotection of the hydroxy groupswhere appropriate. The reduction may be carried out by standard reducingagents known for carrying out this type of reduction (as outlined in J.March, vide supra page 1122), for example, a hydride reagent such aslithium aluminum hydride in an inert solvent, such as an ether, i.e.,tetrahydrofuran, at an non-extreme temperature, for example, at between0° and 100° C. and conveniently at the reflux temperature of the ether.The compound of the formula (VI) may be formed by the reaction of theappropriate acid (ArCOOH) or a suitable reactive acid derivative thereof(as outlined in J. March, vide supra, pages 382-390), for example, anacid halide, in an inert solvent with an amine of the formula (IV) inwhich the hydroxy groups are optionally protected, for example, when thecompound of the formula (IV) is a diol, by an isopropylidene group. Thecompound of the formula (VI) so formed is suitably reduced in situ anddeprotected if necessary to give a compound of formula (I). Thecompounds of the formula ArCOOH can be prepared by methods well known tothose skilled in the art.

3. The reaction of a compound ArCH₂ L (wherein Ar is as hereinbeforedefined and L is a leaving group) with a compound of the formula (IV) ashereinbefore defined. Suitable leaving groups are those defined by J.March, vide supra, pages 325-331, and include halogens such as chlorineand bromine and sulfonic acid derivatives such as p-toluenesulfonate.The reaction is suitably carried out in an appropriate solvent, such asa dipolar aprotic solvent or alcohol at a non-extreme temperature, forexample 50°-100°. The compounds of the formula ArCH₂ L can be preparedby methods well known to those skilled in the art. There is thereforeprovided, as a further aspect of the invention, a method for thepreparation of a compound of formula (I) comprising any method known forthe preparation of analogous compounds, in particular those methodsdefined in (1) to (3) hereinabove.

The compounds of this invention have biocidal activity, e.g., are toxicto certain living cells which are detrimetal to mammals, for examplepathogenic organisms and tumor cells. While the compounds herein havebiocidal activity, it should be appreciated that the range and level ofactivity may vary from compound to compound, and therefore the compoundsare not necessarily equivalent.

This toxicity to pathogenic organisms has been demonstrated by activityagainst viruses (e.g., Herpes simplex 1/vero), fungi(e.g., Candidaalbicans), protozoa (e.g., Eimeria tenella and Trichomonas vaginalis),bacteria (e.g., Mycoplasma smegmatis and Streptococcus pyogenes), andhelminths (e.g., Nippostrongylus brasiliensis). The antitumor activityof compounds of formula (I) has been demonstrated in a number ofrecognized screens and primarily by activity against ascitic P388/0leukemia.

Preferred compounds of the formula (I) are those which have antitumoractivity. The activity against ascitic tumors, including P388/0, isevidenced by reduction of tumor cell number in mammals (for example,mice bearing ascitic tumors) and consequent increase in survivalduration as compared to an untreated tumor bearing control group.Antitumor activity is further evidenced by measurable reduction in thesize of solid tumors following treatment of mammals with the compoundsof this invention compared to the tumors of untreated control tumorbearing animals. Compounds of formula (I) are active against murinetumors such as lymphocytic leukemia P388/0, lymphocytic leukemia L1210,melanotic melanoma B16, P815 mastocytoma, MDAY/D2 fibrosarcoma, colon 38adenocarcinoma, M5076 rhabdomyosarcoma and Lewis lung carcinoma.

Activity in one or more of these tumor tests has been reported to beindicative of antitumor activity in man (A. Goldin et al., in Methods inCancer Research ed. V. T. DeVita Jr. and H. Busch, 16 165, AcademicPress, N.Y. 1979).

There are sublines of P388/0 which have been made resistant to thefollowing clinically useful agents: cytosine arabinoside, doxorubicin,cyclophosphamide, L-phenylalanine mustard, methotrexate, 5-fluorouracil,actinomycin D, cis-platin and bis-chloroethylnitrosourea. Compounds ofthis invention show potent activity against these drug-resistant tumorsusing the procedure for P388/0 above.

Compounds of formula (I) have also been found to be active against humantumor cells in primary cultures of lung, ovary, breast, renal, melanoma,unknown primary, gastric, pancreatic, mesothelioma, myeloma, and coloncancer. As used herein "cancer" is to be taken as synonymous with"malignant tumor" or more generally "tumor" unless otherwise noted. Thisis a procedure in which the prevention of tumor cell colony formation,i.e., tumor cell replication, by a drug has been shown to correlate withclinical antitumor activity in man (D. D. Von Hoff et al., CancerChemotherapy and Pharmacology 6, 265 (1980); S. Salmon and D. D. VonHoff, Seminars in Oncology, 8, 377 (1981).

Compounds of formula I which have been found to have antitumor activityintercalate in vitro with DNA (this property is determined byviscometric methods using the procedure of W. D. Wilson et al., NucleicAcids Research 4, 2697 (1954) and a log P as calculated by the method ofC. Hansch and A. Leo in Substituent Constants for Correlation Analysisin Chemistry and Biology, John Wiley and Sons, N.Y. 1979, lying in therange between -2.0 and +2.5 .

As has been described above, the compounds of the present invention areuseful for the treatment of animals (including humans) bearingsusceptible tumors. The invention thus further provides a method for thetreatment of tumors in animals, including mammals, especially humans,which comprises the administration of a clinically useful amount ofcompound of formula (I) in a pharmaceutically useful form, once orseveral times a day or other appropriate schedule, orally, rectally,parenterally, or applied topically.

In addition, there is provided as a further, or alternative, aspect ofthe invention, a compound of formula (I) for use in therapy, for exampleas an antitumor agent.

The amount of compound of formula (I) required to be effective as abiocidal agent will, of course, vary and is ultimately at the discretionof the medical or veterinary practitioner. The factors to be consideredinclude the condition being treated, the route of administration, thenature of the formulation, the mammal's body weight, surface area, ageand general condition, and the particular compound to be administered. Asuitable effective antitumor dose is in the range of about 0.1 to about120 mg/kg body weight, preferably in the range of about 1.5 to 50 mg/kg,for example 10 to 30 mg/kg. The total daily dose may be given as asingle dose, multiple doses, e.g., two to six times per day, or byintravenous infusion for a selected duration. For example, for a 75 kgmammal, the dose range would be about 8 to 9000 mg per day, and atypical dose would be about 2000 mg per day. If discrete multiple dosesare indicated, treatment might typically be 500 mg of a compound offormula (I) given 4 times per day in a pharmaceutically usefulformulation.

While it is possible for the active compound (defined herein as compoundof formula (I), or ether, ester, or salt thereof) to be administeredalone, it is preferable to present the active compound in apharmaceutical formulation. Formulations of the present invention, formedical use, comprise an active compound together with one or morepharmaceutically acceptable carriers thereof and optionally othertherapeutical ingredients. The carrier(s) must be pharmaceuticallyacceptable in the sense of being compatible with the other ingredientsof the formulation and not deleterious to the recipient thereof.

The present invention, therefore, further provides a pharmaceuticalformulation comprising a compound of formula (I) (in the form of thefree base, ether, or ester derivative or a pharmaceutically acceptableacid addition salt thereof) together with a pharmaceutically acceptablecarrier therefore.

There is also provided a method for the preparation of a pharmaceuticalformulation comprising bringing into association a compound of formula(I), an ether, ester, or pharmaceutically acceptable salt thereof, and apharmaceutically acceptable carrier therefore.

While the antitumor activity of the compounds of formula (I) is believedto reside in the free base, it is often convenient to administer an acidaddition salt of a compound of formula (I).

The formulations include those suitable for oral, rectal or parenteral(including subcutaneous, intramuscular and intravenous) administration.Preferred are those suitable for oral or parenteral administration.

The formulations may conveniently be presented in unit dosage form andmay be prepared by any of the methods well known in the art of pharmacy.All methods include the step of bringing the active compound intoassociation with a carrier which constitutes one or more accessoryingredients. In general, the formulations are prepared by uniformly andintimately bringing the active compound into assocation with a liquidcarrier or a finely divided solid carrier or both and then, ifnecessary, shaping the product into desired formulations.

Formulations of the present invention suitable for oral administrationmay be presented as discrete units such as capsules, cachets, tablets orlozenges, each containing a predetermined amount of the active compound;as a powder or granules; or a suspension in an aqueous liquid ornon-aqueous liquid such as a syrup, an elixir, an emulsion or a draught.

A tablet may be made by compression or molding, optionally with one ormore accessory ingredients. Compressed tablets may be prepared bycompressing in a suitable machine the active compound in a free-flowingform such as a powder or granules, optionally mixed with a binder,lubricant, inert diluent, surface active or dispersing agent. Moldedtablets may be made by molding in a suitable machine, a mixture of thepowdered active compound with any suitable carrier.

A syrup may be made by adding the active compound to a concentrated,aqueous solution of a sugar, for example sucrose, to which may also beadded any accessory ingredients. Such accessory ingredient(s) mayinclude flavorings, an agent to retard crystallization of the sugar oran agent to increase the solubility of any other ingredient, such as apolyhydric alcohol for example glycerol or sorbitol.

Formulations for rectal administration may be presented as a suppositorywith a conventional carrier such as cocoa butter.

Formulations suitable for parenteral administration convenientlycomprise a sterile aqueous preparation of the active compound which ispreferably isotonic with the blood of the recipient. Such formulationssuitably comprise a solution of a pharmaceutically and pharmacologicallyacceptable acid addition salt of a compound of the formula (I) that isisotonic with the blood of the recipient. Thus, such formulations mayconveniently contain distilled water, 5% dextrose in distilled water orsaline and a pharmaceutically and pharmacologically acceptable acidaddition salt of a compound of the formula (I) that has an appropriatesolubility in these solvents, for example the hydrochloride, isethionateand methanesulfonate salts, preferably the latter.

Useful formulations also comprise concentrated solutions or solidscontaining the compound of formula (I) which upon dilution with anappropriate solvent give a solution suitable for parental administrationabove.

In addition to the aforementioned ingredients, the formulations of thisinvention may further include one or more accessory ingredient(s)selected from diluents, buffers, flavoring agents, binders, surfaceactive agents, thickeners, lubricants, preservatives (includingantioxidants) and the like.

The following examples are provided by the way of illustration of thepresent invention and should in no way be construed as a limitationthereof.

GENERAL COMMENTS

All solvents were reagent grade and used without further purificationwith the following exceptions. THF was dried by distillation from Na/Kalloy under nitrogen (N₂) and used immediately. Toluene (PhCH₃) wasdistilled from CaH₂ under N₂ and stored over 3Å molecular sieves.Chemicals used were reagent grade and used without purification unlessnoted. The full name and address of the suppliers of the reagents andchemicals is given when first cited. After this, an abbreviated name isused.

Preparative HPLC was carried out on a Water's Prep LC/System 500Amachine using two 500 g silica gel (SiO₂) cartridges unless otherwisenoted. Plugs of SiO₂ used for purifications were "flash chromatography"SiO₂ (Merck & Co., Inc., Merck Chemical Division, Rahway, NJ 07065,Silica Gel 60, 230-400 mesh). In this precedure, an appropriate volumesintered glass funnel was filled approximately 3/4 full with the SiO₂and packed evenly by tapping the outside of the funnel. A piece offilter paper was then placed on top of the SiO₂ and a solution of thematerial to be purified applied evenly to the top. Gentle suctionthrough a filter flask moved the eluting solvent through the plugrapidly. The appropriate size fractions were combined as needed andfurther manipulated.

General procedures are described in detail. Analogous procedures showmelting point (mp), recrystallization solvents, and elemental analyses(all elements analyzing within a differnece of ≦0.4% of the expectedvalue). Any changes to the procedure such as solvent, reactiontemperature, reaction time, or workup are noted.

NMR (¹ H, ¹³ C), IR and MS data of all new products were consistent withthe expected and proposed structures. The positions assigned tostructural isomers were unequivocally determined by a number of NMRtechniques. All final products were dried in a vacuum oven at 20 mm Hgpressure at the temperature indicated overnight (12-16 h). Alltemperatures are in degrees Celsius. Other abbreviations used are: roomtemperature (RT), absolute (abs.), round bottom flask (RB flask),minutes (min), hours (h).

EXAMPLE 1. -2-[1-DIBENZOTHIOPHENYLMETHYL)AMINO]-2-METHYL-1,3-PROPANEDIOLHYDROCHLORIDE

To a RB flask equipped with magnetic stirring bar, condenser,thermometer, Dean-Stark trap, N₂ inlet line wiht bubbler was addeddibenzothiophene-1-carbaldehyde (M. L. Tedjamulia et al., J. Het. Chem.21, 321(1984), 10.0 g, 65.7 mmol), 2-amino-2-methyl-1,3-propanediol(Aldrich Chemical Co., P. O. Box 2060, Milwaukee, WI 53201, 6.91 g, 65.7mmol, p-toluenesulfonic acid monohydrate (Aldrich, 0.1 g) and PhCH₃ (300mL). The mixture was stirred at reflux with removal of H₂ O for 3 h (oruntil no more H₂ O collects). Most of the PhCH₃ was then removed bydistillation (200 mL).

The mixture was then cooled in an ice bath and diluted with abs. EtOH(200 mL) and cooled. Solid NaBH₄ (MCB Manufacturing Chemists, Inc., 2909Highland Ave., Cincinnati, OH 45212, 2.49 g, 65.7 mmol) was added in oneportion to the mixture. The ice bath was then removed, the reactionallowed to warm to room temperature and then stirred overnight. Thesolvent was then removed from the reaction mixture by rotary evaporationto give a crude solid. This was shaken vigorously with warm H₂ O (500mL) and allowed to cool to RT, filtered and washed with additional H₂ Oand placed in a vacuum oven overnight (80°). The crude solid wastransferred to flask and dissolved in a mixture of CH₃ OH and gaseousHCl dissolved in abs. EtOH, filtered and diluted to 2 L with Et₂ O. Thewhite solid was recrystallized two additional times from CH₃ OH/Et₂ O(400 mL/600 mL), filtered and washed with additional Et₂ O (300 mL) andplaced in a vacuum oven at 80° overnight to give a total of 7.38 g(33.2% yield) of2-[(1-dibenzothiophenylmethyl)-amino]-2-methyl-1,3-propanediolhydrochloride, mp 236-237°, (C,H,N.Cl,S).

Other compounds which were isolated as their methanesulfonates wereproduced by treating the crude free base with methanesulfonic acid(99.5%, Morton Thiokol, Inc.- Alfa Products, P.O. Box 299, 152 AndoverStreet, Danvers, MA 01923), followed by crystallization as describedabove. For other preparations alternative solvents such as abs. EtOH andi-PrOH were used in combination with Et₂ O or hexane as thecrystallization solvents.

EXAMPLE 2. 2-[(2-DIBENZOTHIOPHENYLMETHYL)AMINO]-2-METHYL-1,3-PROPANEDIOLHYDROCHLORIDE

Using the procedure outlined in Example 1, dibenzothiophene-2-carbaldehyde (E. Campaigne and J. Ashby, J. Het. Chem. 6, 517 (1969)and 2-amino-2-methyl-1,3-propanediol (Aldrich) gave a 33.1% yeild of2-[(2-dibenzothio-phenylmethyl) amino]-2-methyl-1,3-propanediolhydrochloride, mp 194-194.5°, (C,H,N,Cl,S), (CH₃ OH/Et₂ O).

EXAMPLE 3 2-[(4-Dibenzothiophenylmethyl)amino]-2-methyl-1,3-propanediolhydrochloride

Using the procedure outlined in Example 1,dibenzothiophene-4-carbaldehyde (M. L. Tedjamulia et al., J. Het. Chem.20, 861 (1983)) and 2-amino-2-methyl1,3-propanediol (Aldrich) gave a38.2% yield of2-[(4-dibenzothiophenylmethyl)amino]-2-methyl-1,3-propanediolhydrochloride, mp 209°-210° (C,H,N,Cl,S), (EtOH/Et₂ O).

EXAMPLE 4 2-[(1-Dibenzofuranylmethyl)amino]-2-methyl-1,3-propanediol

4A. Dibenzofuran-1-carbaldehyde

Dibenzofuran (Aldrich) was formylated using the procedure of A. Riecheet al., Chem. Ber. 93, 88 (1960). The crude product isolated in 83%yield contained mainly dibenzofuran-2-carbaldehyde and a lesser amountof dibenzofuran-1-carbaldehyde. A large proportion ofdibenzofuran-2-carbaldehyde was removed by recrystallization of thecrude product from 95% EtOH. The filtrate was concentrated andchromatographed on SiO₂ using PhCH₃ as the eluting solvent. The firstaldehyde fractions contained dibenzofuran-1-carbaldehyde; laterfractions contained the remaining dibenzofuran-2-carbaldehyde. Thefractions containing the 2-aldehyde were crystallized from CH₂ Cl₂/hexane to give a 43.2% overall yield of dibenzofuran-2-carbaldehyde, mp71°-73°, (C,H). The fractions containing the 1-aldehyde were alsocrystallized from CH₂ Cl₂ /hexane to give a 3.8% yield ofdibenzofuran-1-carbaldehyde, mp 66°-68°, (C,H).

4B. 2-[(1-Dibenzofuranylmethyl)amino]-2-methyl-1,3-propanediolhydrochloride

Using the procedure outlined in Example 1, dibenzofuran-1-carbaldehyde(4A) and 2-amino-2-methyl-1,3-propanediol (Aldrich) gave a 41.4% yieldof 2-[(1-dibenzofuranylmethyl)amino]-2-methyl-1,3-propanediolhydrochloride, mp 237°-238°, (C,H,N,Cl), (CH₃ OH/Et₂ O).

EXAMPLE 5 2-[(2-Dibenzofuranylmethyl)amino]-2-methyl-1,3-propanediolhydrochloride

Using the procedure outlined in Example 1, dibenzofuran-2-carbaldehyde(J. Garmatter and A. E. Siegrist, Helv. Chim. Acta 57, 945 (1974)) and2-amino-2-methyl-1,3-propanediol (Aldrich) gave a 56.4% yield of2-[(2-dibenzofuranylmethyl)amino]-2-methyl-1,3-propanediolhydrochloride, mp 199°-201°, (C,H,N,Cl), (EtOH/Et₂ O).

EXAMPLE 62-[(Naphtho[2,3-b]thiophen-4-ylmethyl)amino]-2-methyl-1,3-propanediol

6A. Naphtho[2,3-b]thiophen-4-carbaldehyde

Naphtho[2,3-b]-thiophene (H. G. Pars Pharmaceutical Laboratories, Inc.,763 Concord Ave., Cambridge, MA 02138) was formylated using theprocedure of A. Rieche et al., Chem. Ber. 93, 88 (1960) to give amixture of crude naphtho[2,3-b]-thiophen-4-carbaldehyde andnaphtho[2,3-b]thiophen-9-carbaldehyde in a 4:1 ratio respectively (by ¹H NMR) in 61.6% yield. The mixture could not be separated bychromatography or fractional crystallization. Reduction of the mixturewith NaBH₄ in THF gave a mixture of the corresponding alcohols. Afterpreparative HPLC using PhCH₃ as the eluting solvent and theshave/recycle technique, 4-hydroxymethylnaphtho-[2,3-b]thiophene wasobtained isomerically pure. This material was oxidized using BaMnO₄ togive after workup and crystallization (CH₂ Cl₂ /hexane) 2.95 g (82.7%yield) of naphtho[2,3-b]thiophene-4-carbaldehyde, mp 113°, (C,H,S).

6B.2-[(Naphtho[2,3-b]thiophen-4-ylmethyl)amino]-2-methyl-1,3-propanediolhydrochloride.0.05 H₂ O

Using the procedure outlined in Example 1,naphtho[2,3-b]thiophen-4-carbaldehyde (6A) and2-methyl-2-amino-1,3-propanediol (Aldrich) gave a 56.6% yield of2-[(naphtho[2,3-b]thiophen-4-ylmethyl)amino]-2-methyl-1,3-propanediolhydrochloride.0.05 H₂ O, mp 205°-207° (dec), (C,H,N,Cl,S) (EtOH/Et₂ O).

EXAMPLE 72-Methyl-2-[(naphtho[2,1-b]thiophen-5-ylmethyl)amino]1,3-propanediol

7A. Methyl 5-formylnaphtho[2,1-b]thiophene-2-carboxylate

Methyl naphtho[2,1-b]thiophene-2-carboxylate (E. Campaigne and R. E.Cline, J. Org. Chem. 21, 39 (1956) was formylated using the procedure ofRieche et al., Chem. Ber. 93, 88 (1960) to give a 52.4% yield of methyl5-formylnaphtho-[2,1-b]-thiophene-2-carboxylate, mp 196°-198°, (C,H,S),(CH₂ Cl₂ /hexane).

7B. Naphtho[2,1-b]thiophene-5-carbaldehyde

To a RB flask equipped with magnetic stirring bar, condenser and N₂inlet line with bubbler was added methyl5-formylnaphtho-[2,1-b]thiophene-2-carboxylate (7A, 9.75 g, 36 mmol),KOH (85%, Mallinckrodt Co., St. Louis, Mo. 63147, 18.0 g, 320 mmol), CH₃OH (40 mL) and H₂ O (80 mL). The mixture was refluxed for 1.5 h, cooledand neutralized with 3N HCl (500 mL). A yellow solid formed which wasfiltered and washed with H₂ O (3×300 mL) and dried in a vacuum ovenovernight to give crude 5-formylnaphtho-[2,1-b]thiophene-2-carboxylicacid in quantitative yield. This material was then slurried withquinoline (Mallinckrodt, 60 mL) and cuprous oxide (MCB, 6.2 g, 43.3mmol) and heated to 185° in an oil bath for 1 h. The reaction mixturewas allowed to cool to RT then partitioned between Et₂ O (500 mL) andconcentrated HCl (200 mL) containing saturated NH₄ Cl (100 mL). Thelayers were separated and the aqueous layer extracted with additionalEt₂ O (500 mL). The Et₂ O layers were combined and washed in successionwith 1N HCl (300 mL), H₂ O (2×300 mL) and saturated NaCl solution (2×300mL), dried (MgSO₄), filtered and concentrated to give a light browncrude solid. After chromatography on SiO₂ using CHCl₃ /hexane as theeluting solvent and crystallization (CHCl₃ /cyclohexane) there wasobtained 4.98 g (65.2% yield) of naphtho[2,1-b]thiophene-5-carbaldehyde,mp 101°-102°, (C,H,S).

7C.2-Methyl-2-[(naphtho[2,1-b]thiophen-5-ylmethyl)amino]-1,3-propanediolhydrochloride

Using the procedure outlined in Example 1,naphtho[2,1-b]-thiophene-5-carbaldehyde (7B) and2-methyl-2-amino-1,3-propanediol (Aldrich) gave an 80.9% yield of2-methyl-2-[(naphtho[2,1-b]thiophen-5-ylmethyl)amino]1,3-propanediolhydrochloride, mp 208.5°-210° (dec) (C,H,N,Cl,S), (i-PrOH/Et₂ O).

EXAMPLE 8Methyl-2-[(naphtho[2,1-b]thiophen-2-ylmethyl)amino]1,3-propanediolhydrochloride

Using the procedure outlined in Example 1,naphtho[2,1-b]-thiophene-2-carbaldehyde (K. Clarke et al., J. Chem. Soc.C 537 (1969)) and 2-methyl-2-amino-1,3-propanediol (Aldrich) gave a75.2% yield of2-methyl-2-[(naphtho[2,1-b]thiophen-2-ylmethyl)amino]-1,3-propanediolhydrochloride, mp 189°-190°, (C,H,N,Cl,S), (EtOH/Et₂ O).

EXAMPLE 92-Methyl-2-[(naphtho[1,2-b]thiophen-5-ylmethyl)amino]1,3-propanediolhydrochloride

Using the procedure outlined in Example 1,naphtho[1,2-b]-thiophene-2-carbaldehyde (M. L. Tedjamulia et al., J.Het. Chem. 20, 1143 (1983)) and 2-methyl-2-amino-1,3-propanediol(Aldrich) gave a 53.3% yield of2-methyl-2-[(naphtho[1,2-b]thiophen-yl-methyl)amino]-1,3-propanediolhydrochloride, mp 224°-224.5°, (C,H,N,Cl,S), (CH₃ OH/Et₂ O).

EXAMPLE 102-Methyl-2-[(naphtho[2,1-b]thiophen-5-ylmethyl)amino]-1,3-propanediol

10A. Methyl 5-formyl-naphtho[1,2-b]thiophene-2-carboxylate

Using the procedure outlined in Example 7A, methylnaphtho[1,2-b]-thiophene-2-carboxylate (E. Campaigne and R. E. Cline, J.Org. Chem. 21, 39 (1956) gave a 61.0% yield of methyl5-formylnaphtho[1,2-b]thiophene-2-carboxylate, mp 207.5°-208.5°,(C,H,S), (CH₂ Cl₂ /hexane).

10B. Naphtho[1,2-b]thiophene-5-carbaldehyde

Using the procedure outlined in 7B, methylnaphtho[1,2-b]-thiophene-2-carboxylate (10A) gave a 61.9% yield ofnaphtho[1,2-b]thiophene-5-carbaldehyde, mp 96°-96.5°, (C,H,S), (CH₂ Cl₂/hexane).

10C.2-Methyl-2-[(naphtho[2,1-b]thiophen-5-ylmethyl)amino]-1,3-propanediolhydrochloride

Using the procedure outlined in Example 1,naphtho[1,2-b]thiophene-5-carbaldehyde (10B) and2-methyl-2-amino-1,3-propanediol (Aldrich) gave a 61.3% yield of2-methyl-2-[(naphtho[1,2-b]thiophen-5-ylmethyl)amino]-1,3-propanediolhydrochloride, mp 196°-198° (dec), (C,H,N,Cl,S), (EtOH/Et₂ O).

EXAMPLE 112-Methyl-2-[(naphtho[2,1-b]thiophen-5-ylmethyl)amino]-1,3-propanediol

11A. Naphtho[1,2-b]furan-2-methanol

To a RB flask equipped with magnetic stirring bar, reflux condenser, N₂inlet line with bubbler was added ethylnaphtho[1,2-b]furan-2-carboxylate (H. G. Pars PharmaceuticalLaboratories, Inc., 6.85 g, 28.5 mmol), lithium borohydride (Aldrich,0.62 g, 28.5 mmol) and dry THF (400 mL). The mixture was stirred atreflux for 6 h and then poured into H₂ O (1 L). The reaction mixture wasacidified with 1N HCl and the resulting white solid was filtered, washedwith additional H₂ O (500 mL) then dissolved in CH₂ CL₂ (500 mL), dried(Na₂ SO₄), filtered, concentrated to 200 mL and diluted to 500 mL withhexane. The resulting material was filtered, washed with hexane (100mL), and placed in a vacuum oven overnight (80°) to give a total of 4.8g (69.7%) of naphtho[1,2-b]furan-2-methanol, mp 105.5°-107°, (C,H).

11B. Naphtho[1,2-b]furan-2-carbaldehyde

To a RB flask equipped with magnetic stirring bar, reflux condenser, N₂inlet line with bubbler was added naphtho[1,2-b]furan-2-methanol (11A,4.8 g, 24.2 mmol), barium manganate (Aldrich, 12.4 g, 48 mmol) and dryCH₂ Cl₂ (500 mL). The mixture was refluxed for 6 h, filtered and theresulting dark yellow solution filtered through a small plug of SiO₂ toremove inorganic salts and polar materials. The solvent was then removedby rotary evaporation and the crude material recrystallized using CH₂Cl₂ /pentane to give after drying 4.02 g (84.7% yield) ofphenanthro[1,2-b]furan-2-carbaldehyde, mp 123°, (C,H).

11C. 2-Methyl-2-[(naphtho[1,2-b]furan-2-ylmethyl)amino]-1,3-propanediolhydrochloride

Using the procedure outlined in Example 1,naphtho[1,2-b]-furan-2-carbaldehyde (11B) and2-methyl-2-amino-1,3-propanediol (Aldrich) gave a 43.4% yield of2-methyl-2-[(naphtho[1 2-b]furan-2-ylmethyl)amino]-1,3-propanediolhydrochloride, mp 197°-199° (dec), (C,H,N,Cl), (EtOH/Et₂ O).

EXAMPLE 122-Methyl-2-[(naphtho[2,1-b]furan-2-ylmethyl)amino]-1,3-propanediolhydrochloride

Using the procedure outlined in Example 1,naphtho[2,1-b]furan-2-carbaldehyde (G. Giovanninetti et al., Farmaco,Ed. Sci. 36, 94 (1981) and 2-methyl-2-amino-1,3-propanediol (Aldrich)gave a 43.4% yield of2-methyl-2-[(naphtho-[2,1-b]furan-2-ylmethyl)amino]-1,3-propanediolhydrochloride, mp 228°-230° (dec), (C,H,N,Cl), (EtOH/Et₂ O).

EXAMPLE 13 2-[(9-Acridinylmethyl)amino]-2-methyl-1,3-propanedioldihydrochloride

Bromination of 9-methylacridine (Lancaster Synthesis, Ltd., P. O. Box1000, Industrial Drive, Wyndham, NH 03087) by the procedure of A.Campbell et al., J. Chem. Soc. 1145 (1958) gave 9-bromomethylacridine.To a RB flask equipped with magnetic stirring bar, condenser, and N₂inlet line with bubbler was added 9-bromomethylacridine (10.5 g, 38.58mmol), 2-amino-2-methyl-1,3-propanediol (Aldrich, 4.06 g, 38.58 mmol),anhydrous K₂ CO₃ (Mallinckrodt, 10.50 g, 76.0 mmol) and abs. EtOH (250mL). The mixture was refluxed for 4 h, cooled and filtered. The solventwas then removed by rotary evaporation. The crude product was dissolvedin CH₃ OH (200 mL) filtered again and diluted to 2 L with Et₂ O. Thedark colored crude product was then recrystallized one additional timefrom CH₃ OH/Et₂ O and then twice from CH₃ OH to give 3.46 g (24.3%yield) of 2-[(9-acridinylmethyl)amino]-2-methyl-1,3-propanedioldihydrochloride.0.6 H₂ O, mp 210°-211° (dec), (C,H,N,Cl).

EXAMPLE 142-[(Acenaphtho[1,2-b]quinolin-10-ylmethyl)amino]-2-methyl-1,3-propanediol

14A. Acenaphtho[1,2-b]quinoline-10-methanol

To a RB flask equipped with magnetic stirring bar, reflux condenser, N₂inlet line with bubbler was added ethylacenaphtho[1,2-b]quinoline-10-carboxylate (H. G. Pars PharmaceuticalLaboratories, Inc., 6.75 g, 23 mmol and dry THF (400 mL). The mixturewas stirred at reflux for 3 h and then poured into H₂ O (1 L). Thereaction mixture was acidified with 1N HCl and the resulting white solidwas filtered, washed with additional H₂ O (500 mL) then dissolved in CH₂Cl₂ (500 mL), dried (Na₂ SO₄), filtered, passed through a small plug ofSiO₂ using CH₂ Cl₂ as the eluting solvent. The appropriate fractionswere combined and the volume reduced to 100 mL and diluted to 400 mLwith hexane. The resulting material was filtered, washed with hexane(100 mL) and placed in a vacuum oven overnight. A total of 5.52 g (81.6%yield) of acenaphtho[1,2-b]quinoline-10-methanol, mp 215°-218° wasobtained which analyzed correctly (C,H,N) for the assigned structure.

14B. Acenaphtho[1,2-b]quinoline-10-carbaldehyde

To a RB flask equipped with magnetic stirring bar, reflux condenser, N₂inlet line with bubbler was aded acenaphtho[1,2-b]quinoline-10-methanol(14A, 2.25 g, 8 mmol), barium manganate (Aldrich, 4.0 g, 16 mmol) anddry CH₂ Cl₂ (1 L). The mixture was refluxed for 24 h, filtered and theresulting dark yellow solution filtered and the solvent removed byrotary evaporation to give a dark green solid. This material wasdissolved in a mixture of EtOAc (700 mL) and THF (200 mL) and passedthrough a small plug of SiO₂ using EtOAc as the eluting solvent. Theappropriate fractions were combined and the solvent removed by rotaryevaporation to give a 71.7% yield ofacenaphtho[1,2-b]quinoline-10-carbaldehyde, mp 245°-246°, (C,H,N).

14C.2-[(Acenaphtho[1,2-b]quinolin-10-ylmethyl)amino]-2-methyl-1,3-propanediolDihydrochloride.1.25 H₂ O

Using the procedure outlined in Example 1,acenaphtho[1,2-b]quinoline-10-carbaldehyde (14B) and2-methyl-2-amino-1,3-propanediol (Aldrich) gave a 55.7% yield of2-[(acenaphtho[1,2-b]quinolin-10-ylmethyl)amino]-2-methyl-1,3-propanedioldihydrochloride.1.25 H₂ O, mp 242°-245° (dec) (C,H,N,Cl), (CH₃ OH/Et₂O).

ANTITUMOR SCREENING RESULTS

Methods for evaluating the antitumor activity of these compounds areessentially those used in the Tumor Panel by the DevelopmentTherapeutics Program, Division of Cancer Treatment, National CancerInstitute, A. Goldin, et al., Methods in Cancer Research, Vol. XVI, p.165, Academic Press (1979). Some modifications, in dose level andschedule have been made to increase the testing efficiency.

EXAMPLE 15 Lymphocytic Leukemia P388/0 Test

CD2-F₁ mice, of the same sex, weighing 20±3 g, are used for this test.Control and test animals are injected intraperitoneally with asuspension of ˜10⁶ viable P388/0 tumor cells on day 0. In each test,several dose levels which bracket the LD₂₀ of the compound areevaluated; each dose level group contains six animals. The testcompounds are prepared either in physiologic saline containing 0.05%Tween 80 or distilled water containing 5% dextrose and are administeredintraperitoneally on days 1, 5, and 9 relative to tumor implant. Dosesare on a mg/kg basis according to individual animals' body weights. Theday of death for each animal is recorded, the median identified for eachgroup and the ratios of median survival time for treated (T)/control (C)groups are calculated. The criterion for activity is T/C×100≧120%.Results of P388/0 testing are summarized in Table I.

                  TABLE I                                                         ______________________________________                                                 Optimal    T/C × 100%                                          Compound Dose       (Excluding 30 Day                                                                           LD.sub.20                                   of Formula                                                                             (mg/kg)    Survivors)    (mg/kg)                                     ______________________________________                                        1        240        +140          240                                         2        225        +130          200                                         3        275        +155          200                                           4B     225        +140          200                                         5        225        +120          225                                           6B     150        +125          150                                          10C     150        +125          115                                         13       440        +130          490                                         ______________________________________                                    

EXAMPLE 16 Formulation Examples

    ______________________________________                                        A. TABLET                                                                     ______________________________________                                        Compound of Formula I   500.0  mg                                             Pregelatinized Corn Starch                                                                            60.0   mg                                             Sodium Starch Glycolate 36.0   mg                                             Magnesium Stearate      4.0    mg                                             ______________________________________                                    

The compound of formula (I) is finely ground and intimately mixed withthe powdered excipients, pregelatinized corn starch and sodium starchglycolate. The powders are wetted with purified water to form granules.The granules are dried and mixed with the magnesium stearate. Theformulation is then compressed into tablets weighing approximately 600mg each.

    ______________________________________                                        B. TABLET                                                                     ______________________________________                                        Compound of formula (I) 500.0  mg                                             Corn Starch             70.0   mg                                             Lactose                 83.8   mg                                             Magnesium Stearate      4.2    mg                                             Polyvinylpyrrolidone    14.0   mg                                             Stearic Acid            28.0   mg                                             ______________________________________                                    

The compound of formula (I) is finely ground and intimately mixed withthe powdered excipients, corn starch and lactose. The powders are wettedwith a solution of polyvinylpyrrolidone dissolved in a mixture ofpurified water and denatured alcohol to form granules. The granules aredried and mixed with the powdered stearic acid and magnesium stearate.The formulation is then compressed into tablets weighing approximately700 mg each.

    ______________________________________                                        C. CAPSULES                                                                   ______________________________________                                        Compound of formula (I) 500.0  mg                                             Corn Starch             50.0   mg                                             Magnesium Stearate      3.0    mg                                             ______________________________________                                    

The finely divided compound of formula (I) is mixed with powdered cornstarch and wetted with denatured alcohol to densify the powder. Thedried powder is mixed with stearic acid and filled into hard-shellgelatin capsules.

    ______________________________________                                        D. SYRUP                                                                      ______________________________________                                        Compound of formula (I)                                                                              250.0   mg                                             Ethanol                250.0   mg                                             Glycerin               500.0   mg                                             Sucrose                3,500.0 mg                                             Flavoring Agent                q.s.                                           Coloring Agent                 q.s.                                           Preserving Agent       0.1%                                                   Purified Water q.s. to 5.0     mL                                             ______________________________________                                    

The compound of formula (I) is dissolved in the ethanol, glycerin, and aportion of the purified water. The sucrose and preserving agent aredissolved in another portion of hot purified water, and then thecolouring agent is added and dissolved. The two solutions are mixed andcooled before the flavoring agent is added. Purified water is added tofinal volume. The resulting syrup is throughly mixed.

    ______________________________________                                        E. IV INJECTION                                                               ______________________________________                                        Compound of formula (I)                                                                         5.0 mg                                                      Glycerin          q.s. for isotonicity                                        Preservative      0.1%                                                        Hydrochloric Acid or                                                                            as needed for                                               Sodium Hydroxide  pH adjustment                                               Water for Injection                                                                             q.s. to 1 mL                                                ______________________________________                                    

The compound of formula (I) and preservative is added to the glycerinand a portion of the water for injection. The pH is adjusted withhydrochloric acid or sodium hydroxide. Water for injection is added tofinal volume and solution is complete after thorough mixing. Thesolution is sterilized by filtration through a 0.22 micrometer membranefilter and aseptically filled into sterile 10 mL ampules or vials.

What is claimed is:
 1. A compound of the formula (I):

    ArCH.sub.2 R.sup.1                                         (I)

or a pharmaceutically acceptable acid addition salt thereof wherein Ar is ##STR14## wherein Z is NH, NCH₃ or NEt wherein R¹ contains not more than eight carbon atoms and is a group: ##STR15## wherein m is o or 1: R⁵ is hydrogen; R⁶ and R⁷ are the same or different and each is hydrogen or C₁₋₅ alkyl, or C₁₋₅ alkyl substituted by hydroxy; R⁸ and R⁹ are the same or different and each is hydrogen or C₁₋₃ alkyl; ##STR16## is a five- or six-membered saturated carbocyclic ring; R¹⁰ is hydrogen, methyl or hydroxymethyl; R¹¹, R¹², R¹³ and R¹⁴ are the same or different and each is hydrogen or methyl;
 2. A compound according to claim 1 or a pharmaceutically acceptable acid addition salt thereof wherein R¹ is ##STR17## wherein m is o; R¹⁶ is CH₂ OH, CH(CH₃)OH or CH₂ CH₂ OH; R¹⁷ is hydrogen, C¹⁻³ alkyl or CH₂ OH; R¹⁸ is hydrogen or methyl.
 3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof wherein R¹ is a diol of the formula: ##STR18## wherein R¹⁹ is hydrogen or methyl and R²⁰ is hydrogen, methyl or ethyl.
 4. The compound of claim 3 in which R²⁰ is methyl.
 5. A pharmaceutical composition for use as an anti-tumor agent comprising an effective tumor treatment amount of the compound of claims 1, 2 and 3, together with a pharmaceutically acceptable carrier therefor. 